Guidelines on the diagnosis and management of multiple myeloma

Transcription

1 Guidelines on the diagnosis and management of multiple myeloma British Committee for Standards in Haematology in conjunction with the UK Myeloma Forum (UKMF) Address for correspondence: BCSH Secretary British Society for Haematology 100 White Lion Street London N1 9PF Disclaimer: While the advice and information in these guidelines is believed to be true and accurate at the time of going to press, neither the authors, the British Society for Haematology nor the publishers accept any legal responsibility for the content of these guidelines. Date for guideline review: January 2012 In 2006 guidelines for the diagnosis and management of multiple myeloma were published (Smith et al, 2006). These current guidelines represent a major revision. The guideline has been split into 2 documents focussing on the Diagnosis and management of multiple myeloma and Symptomatic and supportive care. They are designed to be used together and to complement each other. Page 1

2 Writing group: Jenny Bird 1, Roger Owen 2, Shirley d Sa 3, John Snowden 4, Guy Pratt 5, Tim Littlewood 6, John Ashcroft 6, Kwee Yong 7, Gordon Cook 8, Sylvia Feyler 9, Faith Davies 10, Gareth Morgan 11, Jamie Cavenagh 12, Eric Low 13, Judith Behrens Avon Haematology Unit, Bristol Haematology and Oncology Centre, Bristol 2. Department of Haematology, Leeds Teaching Hospitals NHS Trust 3. Department of Haematology, University College Hospital, London 4. Department of Haematology, Sheffield Teaching Hospitals NHS Trust 5. Department of Haematology, Heart of England NHS Trust, Birmingham 6. Department of Haematology, Leeds Teaching Hospitals NHS Trust 7. Department of Haematology, University College Hospital, London 8. Department of Haematology, Leeds Teaching Hospitals NHS Trust 9. Department of Haematology, Calderdale and Huddersfield NHS Trust 10. Haemato-oncology Unit, Royal Marsden Hospital, London 11. Haemato-oncology Unit, Royal Marsden Hospital, London 12. Department of Haematology, St. Bartholomew s Hospital, London 13. Myeloma UK, Edinburgh 14. Department of Haematology, St Helier Hospital, Carshalton, Surrey Declarations of Interest: All the authors have filled in a declaration of interest from which has been reviewed by the chair of the BCSH Haemato OncologyTask Force and the chair of BCSH and none of the authors are considered to have a conflict of interest with regards to the recommendations made in this guideline. Page 2

3 Contents 1 Methodology, epidemiology and clinical presentation 2 Diagnosis, prognostic factors and disease monitoring 3 Imaging techniques in myeloma 4 Management of common medical emergencies in myeloma patients 5 Myeloma bone disease 6 Renal impairment 7 Induction therapy including management of major toxicities and stem cell... harvesting 8 Management of refractory disease 9 High dose therapy and autologous stem cell transplantation 10 Allogeneic stem cell transplantation 11 Maintenance therapy 12 Management of relapsed myeloma including drugs in development 13 Patient Information and Support The key areas that are covered comprehensively in the document entitled Guidelines for Supportive Care in Myeloma 2009 are listed below: Anaemia Haemostasis and thrombosis issues Pain management Peripheral neuropathy Other symptom control gastrointestinal, sedation/fatigue, mucositis Bisphosphonate-induced osteonecrosis of the jaw Complementary therapies End of life care Page 3

4 1. Methodology, epidemiology and clinical presentation 1.1 Methodology The production of these guidelines involved the following steps: Establishment of working groups in the topic areas detailed above followed by review of key literature to 30 th June 2010 including Cochrane database, Medline, internet searches and major conference reports Development of key recommendations based on randomised, controlled trial evidence. In the absence of randomised data, recommendations were developed on the basis of literature review and a consensus of expert opinion Involvement of patient advocacy through Myeloma UK Review by UKMF Executive and BCSH Committees Review by a BSH sounding board Levels of evidence and grades of recommendation are those of the US Agency for Healthcare Research and Quality (see Appendix 1). In preparing these guidelines the authors have considered overall cost-effectiveness of recommended interventions as well as clinical efficacy data but formal health economic assessments have not been carried out. 1.2 Incidence, prevalence and epidemiology The annual incidence of myeloma in the UK is approximately per million ( The overall prevalence is likely to be increasing given the recently published data demonstrating improved survival rates over the last decade (Brenner et al, 2009; Kumar et al, 2008c). The median age at presentation is approximately 70 years. Only 15% of patients are aged less than 60 years. Myeloma has a higher incidence in Afro-Caribbean ethnic groups than in Caucasians but there are few other distinctive epidemiological features. The majority of cases present de novo but it is now recognised that myeloma is preceded by an asymptomatic monoclonal gammopathy of undetermined significance (MGUS) phase in virtually all patients (Landgren et al, 2009). Page 4

5 1.3 Clinical Presentation Presenting clinical features include symptoms of: Bone disease Impaired renal function Anaemia Hypercalcaemia Recurrent or persistent bacterial infection Hyperviscosity Other patients are diagnosed following the incidental detection of a raised erythrocyte sedimentation rate (ESR), plasma viscosity, serum protein or globulin. Patients with suspected myeloma require urgent specialist referral. Spinal cord compression, hypercalcaemia and renal failure are medical emergencies requiring immediate investigation and treatment. The investigation and management of asymptomatic patients found to have an M-protein are discussed in the UKMF/BCSH MGUS guidelines (Bird et al, 2009). 2. Diagnosis, prognostic factors and disease monitoring 2.1 Investigation and diagnosis Investigation of a patient with suspected myeloma should include the screening tests indicated in Table 1, followed by further tests to confirm the diagnosis. Electrophoresis of serum and concentrated urine should be performed, followed by immunofixation to confirm and type any M-protein present. Immunofixation and SFLC assessment are indicated in patients where there is a strong suspicion of myeloma but in whom routine serum protein electrophoresis is negative (Pratt 2008). Quantification of serum M-protein should be performed by densitometry of the monoclonal peak on electrophoresis; immunochemical measurement of total immunoglobulin (Ig) isotype level can also be used and is particularly useful for IgA and IgD M-proteins. Quantification of urinary total protein and light chain excretion can be performed directly on a 24-hour urine collection or calculated on a random urine sample in relation to the urine creatinine. Page 5

6 Quantification of SFLC levels and / ratio is an additional tool for the assessment of light chain production. The serum tests are particularly useful for diagnosis and monitoring of light chain only myeloma (Bradwell et al, 2003) and patients with oligosecretory / non-secretory disease (see Table 2) (Drayson et al, 2001) and in requests for which urine has not been sent to the laboratory. In renal impairment the half life and thus serum concentration of SFLC can increase ten fold and there is often an increased kappa: lambda ratio (Hutchison et al, 2008). A diagnosis of myeloma should be confirmed by bone marrow (BM) assessment. It is recommended that an adequate trephine biopsy of at least 20 mm in length be obtained in all patients as it provides a better assessment of the extent of marrow infiltration than aspirate smears (Al-Quran et al, 2007; Ng et al, 2006). It is recommended that a diagnosis of myeloma be confirmed by the demonstration of an aberrant plasma cell phenotype and / or monoclonality. Plasma cell phenotyping may be performed by flow cytometry and / or immunohistochemistry on trephine sections. The European Myeloma Network have provided practical guidance on the optimal methods for flow cytometry (Rawstron et al, 2008) and rapid and cost effective single-tube assays have been developed (Rawstron et al, 2008). CD138 immunostaining of trephine sections can be useful to determine the extent of infiltration in selected cases (Al-Quran et al, 2007; Ng et al, 2006). All diagnoses should be made or reviewed by an appropriately constituted Multidisciplinary Team (MDT) (NICE, 2003). Cytogenetic and radiological investigations are discussed in sections 2.4 and 3 respectively. Table 1 - Initial investigations in patients with myeloma Screening tests Tests to establish diagnosis Tests to estimate tumour burden and prognosis Tests to assess myelomarelated organ impairment (ROTI) Special tests indicated in some patients Full blood count (FBC), ESR or plasma viscosity Bone marrow aspirate + trephine biopsy with plasma cell phenotyping Fluorescence in situ hybridisation (FISH) analysis Page 6 FBC

7 Urea, creatinine, calcium, albumin Electrophoresis of serum and concentrated urine Quantification of non-isotypic immunoglobuli ns Immunofixati on of serum and urine Quantification of monoclonal protein in serum and urine Albumin - microglobulin Serum urea and creatinine Creatinine clearance (measured or calculated) Calcium Albumin Plasma viscosity Tissue biopsy (or fat pad aspirate) for amyloid (if suspected) SFLC assay in oligosecretory, light chain only and nonsecretory disease X-ray of symptomatic areas Skeletal survey Skeletal survey Quantification of non-isotypic immunoglobuli ns Skeletal survey Magnetic resonance imaging (MRI) Computerise d tomography (CT) scan 2.2 Diagnostic criteria and differential diagnosis A diagnosis of myeloma should be made using the criteria proposed in 2003 by the International Myeloma Working Group (IMWG) which are detailed in Table 2. Table 2- Diagnostic criteria for MGUS, asymptomatic myeloma and symptomatic myeloma (adapted from International Myeloma Working Group, 2003) MGUS Asymptomatic myeloma Symptomatic myeloma Page 7

8 M-protein in serum <30 g/l Bone marrow clonal plasma cells <10 % and low level of plasma cell infiltration in a trephine biopsy (if done) No related organ or tissue impairment ((no end organ damage including bone lesions) M-protein in serum >30 g/l and/or Bone marrow clonal plasma cells >10 % No related organ or tissue impairment (no end organ damage including bone lesions) or symptoms M-protein in serum and/or urine** Bone marrow (clonal) plasma cells or biopsy proven plasmacytoma Myeloma-related organ or tissue impairment (including bone lesions) *If flow cytometry is performed, most plasma cells (> 90%) will show a neoplastic phenotype. Some patients may have no symptoms but have related organ or tissue impairment. ** No specific concentration required for diagnosis. A small percentage of patients have no detectable M-protein in serum or urine but do have myeloma-related organ impairment (ROTI) and increased bone marrow plasma cells (non-secretory myeloma) Table 3 - Myeloma-related organ or tissue impairment (ROTI) (adapted from International Myeloma Working Group, 2003) Clinical effects due to myeloma *Increased calcium levels *Renal insufficiency *Anaemia *Bone lesions Definition Corrected serum calcium >0.25mmol/l above the upper limit of normal or >2.75mmol/l Creatinine>173mmol/l Haemoglobin 2 g/dl below the lower limit of normal or haemoglobin <10 g/dl Lytic lesions or osteoporosis with compression fractures (MRI or CT may clarify) Page 8

9 Other Symptomatic hyperviscosity, amyloidosis, recurrent bacterial infections (> 2 episodes in 12 months) *CRAB (calcium, renal insufficiency, anaemia or bone lesions). These criteria distinguish between myeloma and MGUS principally on the basis of M-protein concentration, percentage of bone marrow plasma cells and presence or absence of myeloma-related organ and tissue impairment (ROTI, Table 3). Other differential diagnoses in patients with M-proteins include solitary plasmacytoma and other B-cell lymphoproliferative disorders. Detailed guidance on the diagnosis and management of solitary plasmacytoma and MGUS are provided in recently published UKMF/BCSH guidelines (Hughes et al, 2009; Bird et al, 2009). Recommendations International Myeloma Working Group diagnostic criteria should be used (Grade C, level IV) Investigation should be based on the tests shown in Table 1 including an assessment of possible myeloma-related organ and tissue impairment (Grade C, level IV) All diagnoses should be made or reviewed by an appropriately constituted MDT(Grade C, level IV) Plasma cell phenotyping by flow cytometry and / or immunohistochemistry on trephine biopsy sections is recommended in all cases (Grade C, level IV) 2.3 Monitoring and indications for starting therapy (Grade C, level IV). Chemotherapy is indicated for the management of symptomatic myeloma defined by the presence of ROTI. Early intervention in patients with asymptomatic myeloma is not required (Hjorth et al, 1993; Riccardi et al, 2000) although chemotherapy may be considered in patients with a rising M-protein concentration in the absence of ROTI. Patients with asymptomatic myeloma require close monitoring under the supervision of a Consultant Haematologist. The overall risk of progression is 10% per year for the first 5 years but interestingly declines in subsequent years (Kyle et al, 2007). The SFLC ratio (<0.125 or >8) Page 9

10 appears to be predictive of outcome and a risk score incorporating bone marrow plasma cell percentage, M-protein concentration and SFLC ratio has been proposed (Dispenzieri et al, 2008). Flow cytometry is also predictive of outcome as the risk of progression is significantly greater when aberrant phenotype plasma cells determined by flow cytometry comprise >95% of total bone marrow plasma cells (Perez-Persona et al, 2007). Recommendations Chemotherapy is only indicated in patients with symptomatic myeloma based on the presence of ROTI (Grade A; Ib) Patients with asymptomatic myeloma should be monitored under the supervision of a Consultant Haematologist. These patients should be offered entry into clinical trials if available. (Grade C; IV) Monitoring of patients with asymptomatic myeloma should include regular (typically 3 monthly) clinical assessment for the emergence of ROTI and measurement of serum and urinary M-protein (and SFLC when indicated). Repeat bone marrow examination and skeletal imaging should be considered prior to the start of treatment (Grade C; IV) 2.4 Prognostic factors and staging in symptomatic myeloma The natural history of myeloma is heterogeneous with survival times ranging from a few weeks to >20 years. Analysis of prognostic factors is essential to compare outcomes within and between clinical trials. The Durie/Salmon staging system was published in 1975 (Durie and Salmon 1975) but has been superseded by the International Staging System (ISS) (Greipp et al, 2005). This defines 3 risk categories determined by the serum concentration of -microglobulin and albumin. The use of staging systems to determine choice of therapy for individual patients remains unproven. Table 4 - International Staging System (ISS) for multiple myeloma (adapted from Greipp et al, 2005) Stage Criteria Median survival in Page 10

11 months I Serum ß 2 microglobulin < 3.5 mg/l 62 months (296 nmol/l) and serum albumin > 3.5 g/dl (35g/l or 532 µmol/l) II Neither I or III* 45 months III Serum ß 2 microglobulin > 5.5 mg/l (465 nmol/l) 29 months Certain cytogenetic and molecular genetic abnormalities have been shown to predict outcome in myeloma. It is generally accepted that the t(4;14), t(14;16) and deletion 17p, demonstrated by fluorescence in situ hybridisation (FISH), confer an adverse outcome in myeloma. It has therefore been proposed that these abnormalities define high-risk myeloma and should be specifically sought at diagnosis in all patients (Fonseca et al, 2009; Munshi et al, 2009). The prognostic significance of chromosome 13 deletions has been difficult to clarify as some studies have suggested that it is only of prognostic significance when demonstrated by conventional karyotyping which significantly underestimates the overall incidence of the abnormality. Emerging data however suggests that the adverse effect of chromosome 13 deletion relates to its close association with high-risk abnormalities particularly the t(4;14) and there is now consensus that conventional karyotyping has little or no added value in the routine setting (Fonseca et al, 2009). Although there are preliminary data to suggest that the adverse effect of these factors may be abrogated by newer agents (San Miguel et al, 2008a), the current international consensus is that further prospective evaluation is required before clinical decisions can be guided by genetic factors (Munshi et al, 2009). A number of groups have used gene expression profiling to define risk in both newly diagnosed and relapsed patients (Mulligan et al, 2007; Shaughnessy et al, 2007) but itsrole in determining treatment decisions is yet to be defined. Baseline SFLC concentration may also provide useful prognostic information (Dispenzieri et al, 2008). It is essential that new prognostic indicators continue to be evaluated in prospective clinical trials. Recommendations Page 11

12 The International Staging System based on serum albumin and 2- microglobulin should be used ( Grade C, level IV) FISH studies are encouraged for all patients at diagnosis as they provide important prognostic information but their role in directing therapy needs further evaluation in prospective clinical trials ( Grade C, level IV) 2.5 Measuring Response to Therapy The European Group for Blood and Bone Marrow Transplant / International Bone Marrow Transplant Registry / American Bone Marrow Transplant Registry (EBMT/IBMTR/ABMTR) criteria (Blade et al, 1998) were updated by the IMWG in 2006 (Durie et al, 2006) and further modifications were proposed in 2009 (Rajkumar et al, 2009b). The uniform response criteria are detailed in table 5. There are two new response categories, stringent complete response (scr) and very good partial response (VGPR). The criteria now incorporate changes in the SFLC assay but only for those patients with non-quantifiable serum or urine M- proteins defined as a serum M-protein of <10g/l and/ or urinary M-protein of <200mg/24hr. In routine clinical practice there is a clear rationale for utilising the SFLC assay to assess response in light chain only disease irrespective of the extent of light chain excretion in the urine (Pratt 2008). The response category Stringent CR (for use in the reporting of clinical trials) has been refined recently to incorporate the use of flow cytometry to detect minimal residual disease on the basis of the presence of an aberrant immunophenotype (Rajkumar et al, 2009b). Low levels of residual disease may also be demonstrated using allele-specific polymerase chain reaction (PCR) and a further new category of molecular CR is proposed which is defined as the absence of disease by sequence specific PCR methods with a sensitivity of Delayed achievement of complete remission (CR) is seen in a significant proportion of patients following high-dose therapy (Davies et al, 2001). The majority of such patients will have IgG M-proteins which have a half life of approximately 23 days, significantly longer than that of IgA (6 days) and free light chains (4 hours) (Drayson et al, 2004). Repeat bone marrow aspirate assessment is required to confirm CR (repeat trephine biopsy is not required under the response criteria but may be needed for accurate Page 12

13 assessment) (Durie et al, 2006) and should be performed in all patients at Day 100 following high-dose therapy in accordance with EBMT standards. Flow cytometric assessment of minimal residual disease at this time point also provides prognostic information (Paiva et al, 2008) and may in the future be used to guide maintenance / consolidation therapies. The definitions of progressive disease and relapse have also been revised by the IMWG (table 6) and include a new category of clinical relapse which reflects the fact that progressive disease (PD) as defined does not necessarily indicate a need for further therapy (Durie et al, 2006). Table 5 - International Myeloma Working Group uniform response criteria (adapted from Durie et al, 2006; Rajkumar et al, 2009b) Response sub-category Response criteria Stringent complete response CR as defined below plus (scr) Normal SFLC ratio Absence of phenotypically aberrant plasma cells by multiparameter flow cytometry Complete response (CR)* Negative immunofixation on the serum and urine Disappearance of any soft tissue plasmacytomas <5% bone marrow plasma cells Very good partial response (VGPR)* Serum and urine M-protein detectable by immunofixation but not on electrophoresis OR >90% reduction in serum M-protein plus reduction in 24 hour urinary M-protein by > 90% or to <100mg/ 24 hour Partial response (PR)* >50% reduction of serum M-protein and reduction in 24 hour urinary M-protein by >90% or to <200mg/24 hour Stable disease (SD) Not meeting criteria for CR, VGPR, PR or progressive disease Note - in patients in whom the only measurable disease (for definitions see below) is by SFLC assay, CR is defined by negative immunofixation and a normal SFLC ratio, VGPR is defined by >90% decrease in the difference between the involved and uninvolved free light chain concentrations and PR by a >50% decrease in the difference between involved and uninvolved SFLC levels. If SFLC assay is also uninformative, PR is defined by >50% reduction in bone marrow plasma cells provided baseline bone marrow plasma cell percentage was >30%. In addition to the above Page 13

14 listed criteria, if present at baseline, a >50% reduction in the size of soft tissue plasmacytomas is also required. Definitions of measurable disease Response criteria for all categories and subcategories of response except CR are applicable only to patients who have measurable disease defined by at least one of the following three measurements: Serum M-protein > 1g/dl (>10 g/l) Urine M-protein >200 mg/24 hours Serum FLC assay: Involved FLC level >10 mg/dl (>100 mg/l) provided serum FLC ratio is abnormal Table 6 - International Myeloma Working Group uniform response criteria: disease progression and relapse (adapted from Durie et al, 2006; Rajkumar et al, 2009b) Relapse Relapse criteria subcategory Progressive disease Requires at least one of the following (PD) >25% increase in serum M-protein in 3 months (absolute increase must be >5g/l) >25% increase in urine M-protein in 3 months (absolute increase must be >200mg/24hour) >25% increase in the difference between involved and uninvolved SFLC levels (applicable only to patients without measurable serum and urine M- protein (absolute increase must be >10mg/dl) >25% increase in bone marrow plasma cell percentage (absolute percentage must be >10%) Development of new bone lesions or soft tissue plasmacytoma Development of hypercalcaemia Clinical relapse Requires at least one of the following Page 14

15 Development of new bone lesions or soft tissue plasmacytoma Increase in size of existing plasmacytomas or bone lesions Any of the following attributable to myeloma: -Development of hypercalcaemia -Development of anaemia (drop in Hb >2g/dl) -Rise in serum creatinine Relapse from CR Requires at least one of the following Reappearance of serum or urine M-protein by immunofixation or electrophoresis Development of >5% plasma cells in the bone marrow Appearance of any other sign of progression (eg new plasmacytoma, new lytic bone lesion) Recommendations Response to therapy should be defined using the IMWG uniform response criteria (Grade C, level IV) The response category scr is recommended only for use in the clinical trial setting (Grade C, level IV) The SFLC assay should be used to assess response in all patients with light chain only, non secretory and oligosecretory disease (Grade C, level IV) 2.6 Rare myelomas The rare myelomas comprise up to 7% of all myelomas and consist of plasma cell leukaemia, IgD, IgE, IgM and non-secretory myeloma. Plasma Cell Leukaemia Plasma cell leukaemia (PCL) may be primary or secondary to multiple myeloma and is characterised by the presence of >20% circulating plasma cells and/or an absolute level of > 2.0x10 9 /l (Kyle et al, 1974). Page 15

16 IgD, E and M Myelomas IgD myeloma may comprise of up to 1.8% of all myelomas (Blade and Kyle 1994; Wechalekar et al, 2005). Diagnosis may be difficult because some patients may present with a very small or no visible monoclonal spike on serum electrophoresis. Care must be exercised to avoid a false diagnosis of non-secretory or light chain only myeloma (Sinclair 2002).The clinical features are similar to that of other myelomas but Bence-Jones proteinuria, extramedullary involvement, lytic lesions and amyloidosis seem to be more frequent (Jancelewicz et al, 1975). Relatively few cases of IgE myeloma have been reported in the literature (Endo et al, 1981; Kairemo et al, 1999) Morris et al, in press). There may be clinical similarities with IgD myeloma and in both conditions the prognosis appears to be poor (Morris et al, in press). With the increased use of bone marrow trephine biopsies and improved immunohistomorphology (Feyler et al, 2008; Konduri et al, 2005), IgM myelomas are being recognised more frequently and may comprise up to 0.4% of all myelomas (Morris et al, in press). It is important that such cases are distinguished from other IgM secreting disorders particularly Waldenstrom macroglobulinaemia (Avet-Loiseau et al, 2003b). There is a high incidence of the t(11;14) and prognosis appears to be poor (Avet-Loiseau et al, 2003a; Feyler et al, 2008; Morris et al, in press). Non-secretory myeloma Non-secretory myeloma poses particular diagnostic difficulties as there is no serum M-protein and no urinary Bence-Jones protein excretion. The serum-free light chain assay is informative in approximately two thirds of patients (Drayson et al, 2001). While the clinical presentation is essentially similar to standard myeloma, anaemia and lytic lesions may be seen more frequently while renal failure is uncommon (Morris et al, in press). 3 Imaging techniques in myeloma Significant advances in available imaging technologies have paralleled developments in therapy for myeloma and may play a more prominent role in determining prognosis in the future (Durie 2006). A detailed guideline for the use of imaging in myeloma has been published (D'Sa et al, 2007). Key recommendations are summarised below. Page 16

17 Recommendations The skeletal survey remains the screening technique of choice at diagnosis (Grade C, level IV) The skeletal survey should include a postero-anterior (PA) view of the chest, antero-posterior (AP) and lateral views of the cervical spine, thoracic spine, lumbar spine, humeri and femora, AP and lateral view of the skull and AP view of the pelvis; other symptomatic areas should be specifically visualized with appropriate views (Grade C, level IV) CT scanning or MRI should be used to clarify the significance of ambiguous plain radiographic findings such as equivocal lytic lesions, especially in parts of the skeleton that are difficult to visualize on plain radiographs, such as ribs, sternum and scapulae (Grade C, level IV) Urgent MRI is the diagnostic procedure of choice to assess suspected cord compression in myeloma patients with or without vertebral collapse (Grade B recommendation; level IIB evidence). Urgent CT scanning is an alternative, when MR imaging is unavailable, intolerable or contraindicated (Grade B; level III) CT or MR imaging is indicated to delineate the nature and extent of soft tissue masses and where appropriate, tissue biopsy may be guided by CT scanning (Grade B; level IIB) There is insufficient evidence to recommend the routine use of positronemission tomography (PET) or 99m Technetium sestamibi (MIBI) imaging. Either technique may be useful in selected cases for clarification of previous imaging findings preferably within the context of a clinical trial (Grade C, level IV) Bone scintigraphy has no place in the routine staging of myeloma (Grade C, level IV) Routine assessment of bone mineral density cannot be recommended, owing to the methodological difficulties of the technique and the universal use of bisphosphonates in all symptomatic myeloma patients (Grade C, level IV). 4 Management of common medical emergencies in myeloma patients 4.1 Hyperviscosity Page 17

18 Hyperviscosity syndrome may develop in patients with high serum paraprotein levels, particularly those of IgA and IgG3 type. Symptoms include blurred vision, headaches, mucosal bleeding and dyspnoea due to heart failure. All patients with high protein levels should undergo fundoscopy which may demonstrate retinal vein distension, haemorrhages and papilloedema. Patients usually have raised plasma viscosity and symptoms commonly appear when it exceeds 4 or 5 mpa. This usually corresponds to a serum IgM level of at least 30 g/l, an IgA level of 40 g/l and an IgG level of 60 g/l (Mehta and Singhal 2003). Plasma viscosity results should not be used to determine the need for plasma exchange as this may result in delay but testing should be carried out both before and after the procedure.symptomatic patients should be treated urgently with plasma exchange; isovolaemic venesection may be useful if plasma exchange facilities are not immediately available. If transfusion is essential, exchange transfusion should be performed. The need for further exchanges over the next few days should be determined by symptoms and requirement for blood transfusion. Rapid reduction of protein levels is mandatory and anti-myeloma treatment should be instituted promptly. Recommendations Symptomatic hyperviscosity should be treated with therapeutic plasma exchange with saline fluid replacement (Grade C, level IV) If plasmapheresis is not immediately available but hyperviscosity symptoms are present, consider isovolaemic venesection with saline replacement as a holding measure (Grade C, level IV) Effective treatment of the underlying disease should be started as soon as possible (Grade C, level IV) 4.2 Hypercalcaemia Up to 30% of myeloma patients present with hypercalcaemia occurring mostly in the context of active disease. Acute hypercalcaemia can present with central nervous system dysfunction (confusion, coma and obtundation), muscle weakness, pancreatitis, constipation, thirst, polyuria, shortening of the Q-T interval on ECG and acute renal insufficiency. Alternative causes of hypercalcaemia should be Page 18

19 considered eg. hyperparathyroidism. Treatment of the underlying disease should be initiated as soon as possible along with active treatment of hypercalcaemia to minimise long term renal damage. The mainstays of treatment are hydration and intravenous bisphosphonates. Mild hypercalcaemia (corrected calcium mmol/l) may be corrected with oral and/or intravenous rehydration. Moderate to severe hypercalcaemia (corrected calcium 2.9mmol/l) requires intravenous rehydration with normal saline. Adequate urine output should be ensured and use of intravenous loop diuretics such as furosemide should be considered to avoid volume overload and heart failure and promote urinary calcium excretion. All patients with moderate to severe hypercalcaemia should receive a bisphosphonate. A randomised controlled trial in patients with hypercalcaemia of malignancy has shown that zoledronic acid is superior to pamidronate (Major et al, 2001). If the calcium remains high after 72 hours a further dose of zoledronic acid may be given. Dose modifications are required in renal impairment and reduced dose pamidronate (30mg) may be more appropriate in patients with severe renal impairment (see Appendix 3). Patients with refractory hypercalcaemia may require corticosteroids and calcitonin. Recommendations in mild hypercalcaemia (corrected calcium mmol/l) re-hydrate with oral and /or iv fluids in moderate-severe hypercalcaemia (corrected calcium >2.9 mmol/l) rehydrate with intravenous fluids and give furosemide if required (grade C; level III) zoledronic acid is the bisphosphonate of choice in the treatment of hypercalcaemia (grade A; level I) 4.3 Cord compression Page 19

20 Compression of the spinal cord from extramedullary foci of disease occurs in 5% of patients with myeloma during the course of their disease (Kyle et al, 2003). Clinical features depend on the nature of the cord compression (due to bony / structural lesion or to soft tissue disease), the spinal level, extent of disease and the rate of development of cord compression but commonly include sensory loss, paraesthesiae, limb weakness, walking difficulty and sphincter disturbance. This is a medical emergency requiring rapid diagnosis and treatment. Upon clinical suspicion of cord compression, dexamethasone 40 mg daily for 4 days should be commenced and MRI obtained as soon as possible. Where MRI is unavailable or impossible due to patient intolerance or contraindication, an urgent CT scan should be performed. The differentiation between soft tissue and bone related cord compression is essential and should be discussed with neurosurgery/orthopaedic teams (depending on local expertise) immediately if there is any question about the need for surgical intervention. Surgery is usually undertaken for emergency decompression in the setting of structural compression and/or to stabilize the spine and is usually consolidated by post-operative radiotherapy. For soft tissue disease local radiotherapy is the treatment of choice and should be commenced urgently, preferably within 24 hours of the diagnosis of cord compression. There are no randomised controlled trials to give guidance on optimal radiotherapy dose and fractionation but a retrospective multi-centre study of 172 myeloma patients has been published and demonstrated a better overall outcome in terms of improvement in motor function for patients treated with at least 30Gy (Rades et al, 2006). Recommendations (all Grade C recommendation; level IV evidence unless shown) Urgent MRI should be performed and neurosurgical or spinal surgical / clinical oncology consultation obtained (Grade C, level IV) Local radiotherapy is the treatment of choice for non-bony lesions and should be commenced as soon as is possible, preferably within 24 hours of the diagnosis. A dose of 30Gy in 10 fractions is recommended (Grade B; level IIb) Page 20

21 Surgery is recommended for emergency decompression in the setting of bony compression and/or to stabilize the spine (Grade C, level IV) If cord compression is a presenting symptom, it is important to concurrently pursue a rapid diagnosis and to institute systemic therapy as soon as possible (Grade C, level IV) 4.4 Early Infection Myeloma is associated with an increased incidence of early infection. This is related to deficits in both humoral and cellular immunity, reduced mobility and performance status which are all associated with both the disease and its treatment. It has been reported that up to 10% of patients die of infective causes within 60 days of diagnosis (Augustson et al, 2005). Neutropenia is not usually a factor in early infection (Augustson et al, 2005) There is increasing evidence showing that high dose steroids in the elderly or in patients with poor performance may be detrimental with increased toxicity and a higher mortality rate in the short-term and consideration should be given to the use of lower doses in this group (Ludwig et al, 2009; Morgan et al, 2009; Rajkumar et al, 2009a). Patient education as well as access to 24 hour specialist advice and treatment is crucial in preventing and managing infection in myeloma. Prevention and management of infection in myeloma patients is discussed in more detail in the supportive care guideline. Recommendations There must be 24-hour access to specialist advice for the patient and/or primary care team (Grade C, level IV) Any febrile myeloma patient should be treated promptly with broadspectrum antibiotics. Intravenous antibiotics are required for severe systemic infection or neutropenic sepsis (Grade C, level IV) Aminoglycosides should be avoided, if possible (Grade C, level IV) There is insufficient evidence to recommend the routine use of prophylactic antibiotics (Grade C, level IV) 5 Myeloma bone disease Page 21

22 5.1 Clinical features of bone disease Bone disease occurs in 80-90% of myeloma patients. The development of bone disease, either focal or diffuse, can result in pain, pathological fractures/spinal cord compression and hypercalcaemia (Coleman 1997; Croucher and Apperley 1998; Terpos and Dimopoulos 2005) Skeletal events compromise mobility and day-to-day independence, decrease quality of life (Cocks et al, 2007; Terpos and Rahemtulla 2004; Vogel et al, 2004) and increase overall treatment costs. 5.2 Bone fractures Long bone fractures require stabilization and subsequent radiotherapy. Radiotherapy is useful to improve pain control and may also promote healing of the fracture site. Where large lytic lesions may cause skeletal instability an orthopaedic opinion should be sought and pre-emptive surgery considered in selected patients. Specialised clinical interventions for pain associated with spinal fractures including vertebroplasty and kyphoplasty are discussed in the supportive care guideline. Recommendations Local radiotherapy is helpful for pain control; a dose of 8 Gy single fraction is recommended (Grade C, level III) Long bone fractures require stabilisation and subsequent radiotherapy; a dose of 8 Gy single fraction is recommended (Grade C, level III) 5.3 Bisphosphonates A Cochrane Review of the use of bisphosphonates in myeloma (Djulbegovic et al, 2002) included data from 10 placebo-controlled trials of clodronate, pamidronate, or etidronate and from a preliminary report of a trial of ibandronate. Based on a metaanalysis of trial data at that time, the conclusion was that adding bisphosphonates to the treatment of myeloma reduces vertebral fractures and pain but does not improve survival. The evidence also suggested a benefit in both patients with and without bone disease at presentation. Randomised trials with etidronate, clodronate, pamidronate, zoledronic acid and ibandronate in myeloma patients have now been published (reviewed in (Terpos et al, 2009)). Oral etidronate has been shown to be ineffective in myeloma and may cause demineralization (Belch et al, 1991). There Page 22

23 are as yet no published randomised studies of risedronate or alendronate, while ibandronate failed to show any effect on fracture rates or survival (Menssen et al, 2002). The trials of sodium clodronate (Lahtinen et al, 1992; McCloskey et al, 2001; McCloskey et al, 1998) demonstrated benefit for up to four years in patients starting chemotherapy for the first time, including patients with no lytic lesions. Studies using the nitrogen containing bisphosphonates have been primarily in patients with more extensive bony disease. Both pamidronate and zoledronic acid have demonstrated their effectiveness in the reduction of skeletal related events (SREs) in this setting (Berenson et al, 2001; Rosen et al, 2001; Rosen et al, 2003). Zoledronic acid and pamidronate appear equally efficacious with regards to SRE prevention although there has been no randomised comparison and no long term analysis of treatment benefit. Zoledronic acid is however associated with greater improvements in skeletal morbidity and normalisation of N-telopeptide of collagen type1 (NTX) in some studies (Rosen et al, 2001). The Medical Research Council (MRC) Myeloma IX trial has recently reported with a median follow up of 3.7 years and demonstrated significant benefits of zoledronic acid over sodium clodronate in reduction of SREs (27% vs 35.3% P=0.0004, and crucially in overall survival (OS) (50 vs 44.5 months, P=0.0118) and progression free survival (PFS) (19.5 vs 17.5 months, P=0.0179) respectively (Morgan et al, 2010). There was however a higher incidence of bisphosphonate associated osteonecrosis of the jaw (BONJ) in the zoledronic acid group (3.5% vs 0.3%). There has also been a suggestion of a survival benefit in the pamidronate trials but this was only demonstrated following subgroup analysis. Adverse effects on renal function have been reported particularly with the nitrogencontaining bisphosphonates (pamidronate and zoledronic acid) and are most likely if the recommended dose or rate of infusion is exceeded (Barri et al, 2004; Berenson et al, 1998; Chang et al, 2003; Rosen et al, 2001). Specific protocols are provided by the manufacturers with regards to administration in patients with renal impairment (see Appendix 3). Oral calcium and vitamin D supplementation is advised with zoledronic acid. There is no recommendation with pamidronate and it should probably be avoided with sodium clodronate as it may impair absorption of the oral bisphosphonate. All Page 23

24 bisphosphonates are associated with a risk of BONJ but particularly the nitrogen containing intravenous preparations. This is discussed in detail in the supportive care guidelines. Treatment in asymptomatic patients There is little published evidence to guide the optimal time point to initiate bisphosphonate treatment. A trial of monthly intravenous pamidronate versus placebo in newly diagnosed patients not requiring chemotherapy suggested a bone protective effect, although other manifestations of progression were not influenced (Musto et al, 2003). Similar results have been suggested with zoledronic acid monthly for one year although one patient did develop BONJ (Musto et al, 2008). Recommendations for bisphosphonate therapy Bisphosphonate therapy is recommended for all patients with symptomatic multiple myeloma, whether or not bone lesions are evident (grade A; level 1b) Zoledronic acid and pamidronate both show efficacy with respect to SRE prevention (grade A; level 1b) but early data regarding prolongation of EFS and OS in a large randomised trial suggest that zoledronic acid should be the bisphosphonate of choice. Sodium clodronate is less effective than zoledronic acid but has a significantly lower incidence of BONJ (grade A; level 1b) There is no consensus regarding the duration of bisphosphonate therapy. The standard of care to date has been indefinite bisphosphonate therapy. However, given the risk of BONJ, it is reasonable to consider stopping therapy under certain circumstances such as those patients who have achieved a CR or VGPR with transplantation and/or a novel therapy combination and have no active bone disease; this should be at the discretion of the treating haematologist. In the absence of definitive data the duration of therapy should take into account individual factors such as remission status, extent of skeletal disease, renal function and patient preference. In patients Page 24

25 who do stop bisphosphonate therapy, therapy should be reinstituted at the time of relapse (grade C; level IV) Renal function should be carefully monitored and doses reduced in line with the manufacturers guidance. For guidance on the use of bisphosphonates in renal impairment, see Appendix 3 At present there is insufficient evidence to make a recommendation for the use of bisphosphonates in patients with asymptomatic myeloma Dental evaluation should be carried out before starting IV bisphosphonate therapy 6 Renal Impairment 6.1 Incidence and pathophysiology Renal impairment is a common and potentially serious complication of myeloma occurring at presentation in 20-25% of patients (Knudsen et al, 1994) and in up to 50% of patients at some time during their disease (Eleutherakis-Papaiakovou et al, 2007; Kyle 1975). It is possible to reverse renal insufficiency in approximately half of patients but the remainder will have some degree of persistent renal impairment and of these, 2-12 % will require renal replacement therapy (Clark et al, 1999). Renal failure occurs as a result of damage caused to renal tubules by free light chains (cast nephropathy, or myeloma kidney ). A variety of other nephrotoxic processes may also contribute to this damage including dehydration, hypercalcaemia, nephrotoxic drugs, and infection (Clark et al, 1999; Haubitz and Peest 2006; Penfield 2006). The risk of renal damage is directly proportionate to the level of urinary free light chain excretion and not attributable to the light chain class or the presence or absence of whole M-proteins. Only 2% of patients without urinary free light chain excretion have renal impairment. This percentage increases to 50% with higher levels of urinary free light chain excretion (Drayson et al, 2006). Patients presenting with renal failure have a high early death rate; of 367 newly diagnosed myeloma patients with serum creatinine >199 mmol/l, 29.4% died within 60 days of diagnosis (Augustson et al, 2005). In this study 43 of 299 deaths within 60 days were attributed wholly to renal failure. It is therefore critically important to Page 25

26 prevent renal failure, or if established, to reverse it as this will significantly improve survival (Knudsen et al, 2000). 6.2 Prevention of Renal Failure Early diagnosis of both new and relapsed myeloma enables early intervention and thus prevention of renal damage (Augustson et al, 2005; Drayson et al, 2006). A diagnosis of light chain only myeloma and of light chain escape may be missed if urine is not sent to the laboratory and serum free light chain levels are not measured (Pratt 2008). Relapse with rising levels of free light chain and no change in whole paraprotein (light chain escape) occurs in 5% of IgG and 15% of IgA myeloma patients (Mead and Drayson 2009). Renal function is optimised by maintenance of a high fluid intake, at least 3 litres/day (Medical Research Council,1984) and all patients should be instructed as to the importance of this throughout the course of the disease. Potentially nephrotoxic drugs, including aminoglycosides and nonsteroidal anti-inflammatory drugs (NSAIDs) should be avoided. 6.3 Early Management of Renal Failure The goal of initial treatment is to remove precipitating causes and to rapidly reduce the light chain load delivered to the kidney tubule. Hypercalcaemia must be corrected with bisphosphonates, used with modified doses because the kidney is their only route of excretion (see Appendix 3). Infection must be treated vigorously, nephrotoxic drugs stopped and patients rehydrated. Dehydration from any cause will increase the concentration of light chains delivered to the renal tubule. Renal recovery can be achieved with intravenous fluid to achieve a urine flow of over 3 litres/ day (MRC,1984). Volume replacement should be guided by monitoring of central venous pressure when renal output is reduced. There is little evidence to support urinary alkalinisation (Iggo et al, 1997).The advice of a nephrologist should be sought if renal function does not improve within 48 hours of initial interventions and there must be clear communication between haematologists and the specialist renal team to optimise outcome. Renal biopsy is desirable to help guide management but is not essential. Page 26

27 Physical removal of light chains by plasma exchange (PE) is theoretically beneficial in cast nephropathy. Data from two early small randomised trials was conflicting (Johnson et al, 1990; Zucchelli et al, 1988) and the results of a further randomised, controlled trial (Clark et al, 2005) were inconclusive. Results of further UK studies of PE and of large pore haemodialysis are awaited. Reducing light chain production from the plasma cell clone is the most effective mechanism of reducing the light chain load to the kidney. High dose dexamethasone alone is effective as a single agent in this setting (Alexanian et al, 1992) and can lead to one hundred fold falls in SFLC within 2 weeks in sensitive disease. Lower levels are associated with renal recovery (Drayson et al, 2009; Hutchison et al, 2008). Oral high dose dexamethasone should be started without delay whilst decisions about definitive chemotherapy are being made. Serum free light chain measurements in the first 2 weeks may identify patients who are not responding to their anti-myeloma therapy. Further work is needed to evaluate how this finding may influence treatment decisions in the future. The high early death rate in patients with myeloma and renal failure is mainly due to infection which is a major preventable cause of death in these patients. Close observation and early and intensive treatment of infective episodes is essential if this early loss is to be improved. Recommendations for initial management of renal failure Vigorously rehydrate with at least 3 litres of normal saline daily Treat precipitating events eg hypercalcaemia, sepsis and hyperuricaemia and discontinue nephrotoxic drugs, particularly NSAIDs. Consider physical methods of removing free light chains from the blood (plasma exchange, large pore haemofiltration) within the context of a clinical trial Administer high dose dexamethasone unless otherwise contraindicated pending initiation of definitive treatment which should be started without delay Monitor serum free light chain levels Identify and treat infection vigorously Patients with renal failure require dose modification of bisphosphonates and the risk of renal adverse events may be greater in patients with impaired Page 27

28 renal function. For guidance on use of bisphosphonates in patients with renal impairment, see Appendix 3. 7 Induction therapy including management of major toxicities and stem cell harvesting The broad aims of treatment in myeloma are to control disease, maximise quality of life and to prolong survival and can be achieved by a combination of specific disease-directed therapy and supportive care. Although high-dose therapy is recommended where possible, many patients will not be able to receive such therapy because of advanced age, co-morbidities or poor performance status. Treatment decisions should be reviewed in an MDT and should take into account individual patient factors and patient choice. The introduction of novel agents such as thalidomide, lenalidomide and bortezomib (usually in combination with dexamethasone) has led to a clear improvement in survival of patients with myeloma (Kumar et al, 2008c). However, much work is needed to determine the best sequence and combinations of therapies. It is therefore essential that wherever possible patients are entered into clinical trials. As many patients are living longer with myeloma, the impact of therapy on quality of life is particularly important. Many studies both in the transplant and non-transplant settings have suggested a link between the maximal response attained and long-term outcome after initial therapy and that increasing the complete remission rate after transplant results in prolonged progression free survival and overall survival (Lahuerta et al, 2008; van de Velde et al, 2007). Improving depth of response is therefore becoming an increasingly important goal. 7.1 Induction therapy prior to high dose therapy (HDT) including management of common side-effects For patients where HDT is planned, or is a possible future option, the aim of induction treatment is to induce high remission rates rapidly and with minimal toxicity and to preserve haemopoietic stem cell function to ensure successful mobilisation of peripheral blood stem cells (PBSC). Page 28